Chiral, bidentate organophosphorus ligand

ABSTRACT

A chiral, bidentate organophosphorus ligand containing a dideoxysaccharide used along with zero valent nickel as a catalyst for enantioselective hydrocyanation. The preferred organophosphorus ligand species is phenyl 2,3-bis-O-(3,5-bis(trifluoromethyl)phenyl)phosphine-4,6-O-benzylidene-B-D-glucopyranoside.

This is a continuation of application Ser. No. 08/201,947, filed Feb.25, 1994; which is, in turn, a division of application Ser. No.07/961,593, filed Oct. 15, 1992, now U.S. Pat. No. 5,312,957; which is,in turn, a division of application Ser. No. 07/790,322, filed Nov. 12,1991, now U.S. Pat. No. 5,175,335.

FIELD OF THE INVENTION

This invention relates to the enantioselective hydrocyanation ofaromatic vinyl compounds to produce nonracemic mixtures of chiralarylpropionitriles; to novel catalyst compositions used therein whichare comprised of zero-valent nickel and chiral, nonracemic carbohydratephosphorus ligands; and to optically pure(S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile which is producedusing the novel process and catalyst compositions.

BACKGROUND OF THE INVENTION

Arylpropionitriles are useful precursors to an important class of chiralarylpropionic acids that are nonsteroidal, antiinflammatory drugs,Tetrahedron, 1986, 42 (15), 4095, J. Org. Chem., 1985, 50, 5370. In mostcases, the beneficial properties of these drugs are believed to arisefrom only one enantiomer and, in some cases, the properties of the otherenantiomer are harmful. Thus selective, synthetic routes to nonracemicmixtures of arylpropionitriles or arylpropionic acids are highlydesirable.

U.S. Pat. Nos. 3,496,215; 3,496,217; 3,496,218; 3,631,191; 3,655,723;3,798,256; 3,846,461; 3,847,959; and 3,903,120 describenonenantioselective alkene hydrocyanation in the presence of low valent,organophosphorous Ni catalysts and, in some cases, Lewis acid promoters.The nickel-catalyzed hydrocyanation of styrene and vinylnapthalenederivatives occurs in a predominantly Markovnikov fashion to generateracemic mixtures of chiral, arylpropionitriles (J. Org. Chem., 1985, 50,5370; Adv. Catal., 1985, 33, 25-31).

Very few examples of enantioselective, transition-metal-catalyzed alkenehydrocyanations have been documented. Reported enantioselectiveinductions pertain primarily to the enantioselective hydrocyanation ofnorbornene derivatives, and only modest product e.e.'s (enantiomericexcesses) have been obtained. The highest e.e. reported for anytransition-metal-catalyzed enantioselective alkene hydrocyanation is 40%for a Pd catalyzed hydrocyanation of norbornene (6% product yield;Organometallics 1988, 7, 1761).

To achieve the enantioselective alkene hydrocyanation of the instantinvention, Applicants have used a class of nickel hydrocyanationcatalyst compositions comprised of zero-valent nickel and chiral,nonracemic bidentate organophosphorus ligands. Such catalysts are notknown to have been used previously in enantioselective hydrocyanation ofaromatic vinyl compounds.

The use of catalyst compositions of zero-valent nickel and chiral,nonracemic O-substituted, bidentate diolphosphorus ligands derived fromchiral diols for the enantioselective hydrocyanation of norbornene havebeen reported in Aust. J. Chem., 19082, 35, 2069; J. Chem. Soc. Commun.,1991, 1292). However, use of such catalysts on aromatic vinyl substratesis not disclosed.

Nonracemic mixtures of chiral, O-substituted diolphosphorus ligandsderived from carbohydrates, such as D-glucose, have been used previouslyas ligands in the catalytic, enantioselective hydrogenation ofα,β-unsaturated acid derivatives. The catalyst compositions of theinstant invention, however, which comprise nickel, are not known in theenantioselective hydrocyanation of alkenes.

In addition, the preparation of racemic2-(6-methoxy-2-naphthalene)propionitrile has been previously reported inSynthetic Commun. 1984, 14, 13655 J. Org. Chem. 1985, 50, 5370, but thepreparation of the pure S enantiomer is not disclosed. Using a preferredembodiment of the process of the invention Applicants have achieved thepreparation of optically pure(S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile.

SUMMARY OF THE INVENTION

Applicants' invention encompasses 1) a process for enantioselectivehydrocyanation of aromatic vinyl compounds wherein nonracemic mixturesof chiral, arylpropionitriles are produced, 2) novel catalystcompositions which are used in the process, and 3) an optically pureproduct of the process:(S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile.

The invention provides a process for enantioselective hydrocyanationcomprising:

reacting an aromatic vinyl compound of the formula

    Ar--CH--CH.sub.2

wherein Ar is an aromatic or heteroaromatic radical which each mayadditionally be substituted with halogen, ether, ester, alcohol, amideor ketone groups;

with a source of HCN;

in the presence of a catalyst composition comprising zero-valent nickeland a chiral, nonracemic, bidentate organophosphorus ligand of theformula

    (R.sup.1).sub.2 --P--R.sup.2 --P--(R.sup.1).sub.2

wherein each R¹ is independently a C₁ to C₂₀ hydrocarbyl, alkoxy, oraryloxy, each optionally substituted with one or more halogen, alkylhalide, ether, ester, carboxy or amide groups; and R² is a hydrocarbylor hydrocarbyloxy, each optionally substituted with one or more halogen,ether, ester, alcohol, amide or ketone groups, or R² is a C₄ to C₄₀carbohydrate, optionally substituted with one or more hydrocarbyl,halogen, ether, ester, alcohol, amide or ketone groups;

to produce a nonracemic nitrile product of the formula ##STR1## whereinAr is defined as above.

The invention further provides a catalyst composition comprising asource of zero-valent nickel and a chiral, nonracemic, bidentateorganophosphorus ligand of the formula

    (R.sup.1).sub.2 --P--O--R.sup.3 --O--P--(R.sup.1).sub.2

wherein each R¹ is independently a C₁ to C₂₀ hydrocarbyl, alkoxy oraryloxy, each optionally substituted with one or more alkyl, cycloalkyl,alkenyl, aralkyl, aryl, halogen, ether, ester, carboxy or amide groups;and R³ is a C₄ to C₄₀ dideoxycarbohydrate, optionally substituted withone or more hydrocarbyl, halogen, ether, ester, alcohol, amide or ketonegroups.

The invention further provides optically pure(S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile.

DETAILED DESCRIPTION OF THE INVENTION

The process of the instant invention, whereby enantioselectivehydrocyanation is accomplished on aromatic vinyl compounds, is useful,for example, to produce any of a class of arylpropionitriles which areprecursors to nonsteroidal, anti-inflamatory drugs such as ibuprofen andnaproxen. The novel catalyst compositions of the instant invention,comprising zero-valent nickel and chiral, nonracemic diolphosphorusligands derived from carbohydrate diols, are useful for accomplishingthe above-described enantioselective hydrocyanation reactions. Opticallypure (S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile is a valuableprecursor to the nonsteroidal, antiinflammatory drug(S)--(-)-2-(6-methoxy-2-naphthalene) propionic acid (naproxen).

By the term "carbohydrate", Applicants mean the class of organiccompounds comprising the general formula (C.H₂ O)_(n), wherein n isequal to or greater than four. The carbohydrate-derived ligands of theinvention are derived from C₄ to C₄₀ carbohydrates includingmonosaccharides, disaccharides and oligosaccharides. Thedideoxymonosaccharide may be dideoxyhexose. The dideoxyhexose may bedideoxyglucose, dideoxygalactose, dideoxypentose, dideoxylactose, anddideoxytrehalose.

By the term "heteroaromatic", Applicants mean a cyclic aromatic compoundcontaining at least one oxygen, nitrogen or sulfur atom in the ring.

By the term "hydrocarbyl", Applicants include all alkyl, aryl, aralkylor alkylaryl carbon substituents, either straight-chained, cyclic, orbranched.

By the terms "substituted hydrocarbyl, substituted alkoxy, orsubstituted aryloxy", Applicants refer to a structure which issubstituted with one or more of the following groups: alkyl, cycloalkyl,alkenyl, aralkyl, aryl, halogen, alkyl halide, ether, ester, carboxy,and amide.

By the term "hydrocarbyloxy", Applicants describe the group --O--R--O--;wherein R is a hydrocarbyl.

In describing a carbohydrate group of the formula O--R--O, the group Ris named by using the prefix "dideoxy" with the name of the parent diolof the formula HO--R--OH. For example, the name 2,3-dideoxyglucoserefers to the group: ##STR2## and accordingly, the correspondingcarbohydrate group O--R--O is: ##STR3##

The suffix -ose- when used in combination with carbohydrate root names,shall include those compounds wherein the OH groups are protected asethers or esters. By this definition, for example, the glucopyranosidestructure shown below is termed "a glucose" ##STR4## wherein Ac is anacetyl.

By the term "substituted styrene", Applicants refer to a styrenemolecule which is substituted with at least one of the following groups:alkyl, cycloalkyl, alkenyl, aralkyl, aryl, halogen, ether, ester,carboxy, amine, and amide.

By the term "chiral", Applicants mean "existing as a pair ofenantiomers". These stereoisomers, designated the R and S isomers, arenonsuperimposable mirror images of one another. A chiral material mayeither contain an equal amount of the R and S isomers in which case itis called "racemic" or it may contain inequivalent amounts of R and Sisomer in which case it is called "optically active", or "nonracemic".

By the term "enantiomeric excess" ("ee"), Applicants mean the absolutedifference between the percent of R enantiomer and the percent of Senantiomer of an optically active compound. For example, a compoundwhich contains 75% S isomer and 25% R isomer will have an enantiomericexcess of 50%.

The term "optically pure" refers to an enantiomeric excess greater than99%.

By the term "enantioselective" Applicants mean the ability to produce aproduct in an optically active form.

The enantioselective hydrocyanation reaction of the invention is carriedout, either as a batch, semi-batch or continuous process, by theaddition of a source of HCN to an aromatic vinyl compound of the formulaAr--CH═CH₂. The reaction is carried out in the presence of a chiral,nonracemic, nickel hydrocyanation catalyst composition to producechiral, nonracemic, arylpropionitriles of the formula Ar--CH(CN)CH₃.##STR5##

The substrates of the invention, described by the formula Ar--CH═CH₂,may be any aromatic or heteroaromatic compound with a vinyl functionalgroup, which is represented by --CH═CH₂. Examples of Ar include, but arenot limited to, phenyl, naphthyl and methoxynaphthyl. Representativeexamples of substrates used in the invention include, but are notlimited to, 2-vinylnaphthalene, 6-methoxy-2-vinylnaphthalene,4-isobutylstyrene and styrene. Further, Applicants contemplate that theprocess of the instant invention may effectively achieveenantioselective hydrocyanation of conjugated alkenes, as well as thearomatic vinyl compounds of the present invention.

The aromatic vinyl substrates of the invention may be made by methodswhich are well-known in the art e.g., Organometallics, 1991, 10,1183-1189 which is hereby incorporated by reference; and some of thesesubstrates are available commercially as well.

For all embodiments of the Applicants' invention the chiral, nonracemic,nickel hydrocyanation catalyst comprises a chiral, nonracemic,organophosphorus ligand and a source of zero-valent nickel. Thezero-valent nickel can be prepared or generated according to techniqueswell-known in the art (U.S. Pat. Nos. 3,496,217; 3,631,191; 3,846,461;3,847,959; and 3,903,120 which are incorporated by reference).Zero-valent nickel compounds that contain ligands which can be displacedby the chiral organophosphorus ligand are a preferred source ofzero-valent nickel. Two such preferred zero-valent nickel compounds areNi(COD)2 (COD is 1,5-cyclooctadiene) and Ni (P (O-o-C₆ H₄ CH₃)₃)₂ (C₂H₄), both of which are known in the art. Alternatively, divalent nickelcompounds may be combined with a reducing agent, and are then able toserve as suitable sources of zero-valent nickel in the reaction.Suitable divalent nickel compounds include compounds of the formula NiY₂where Y is halide, carboxylate, or acetylacetonate. Suitable reducingagents include metal borohydrides, metal aluminum hydrides, metalalkyls, Zn, Fe, Al, Na, or H₂. Elemental nickel, preferably nickelpowder, when combined with a halogenated catalyst, as described in U.S.Pat. No. 3,903,120, is also a suitable source of zero-valent nickel.

The catalyst composition of the invention also comprises, in addition tothe nickel, a chiral, nonracemic, bidentate organophosphorus ligand ofthe formula (R¹)₂ P--R² --P(R¹)₂ wherein each R¹ may independently be aC₁ to C₂₀ hydrocarbyl, alkoxy, or aryloxy, each optionally substituted;and R² may be a C₁ to C₄₀ hydrocarbyl or C₁ -C₄₀ hydrocarbyloxy, eachoptionally substituted with one or more halogen, ether, ester, alcohol,amide or ketone groups, or R² is a C₄ to C₄₀ carbohydrate, optionallysubstituted with hydrocarbyl, halogen, ether, ester, alcohol, amide orketone groups. The preparations of such chiral organophosphorus ligandsare generally known in the art and many of these ligands arecommercially available.

In a more particular embodiment, the process of the invention employs aligand comprising a chiral, nonracemic O-substituted diolphosphorus ofthe formula (R¹)₂ P--R² --P--(R¹)₂ wherein R¹ is defined as above, andR² is a moiety of the formula --O--R³ --O--, wherein R³ is C₁ to C₄₀hydrocarbyl or C₄ to C₄₀ dideoxycarbohydrate, each optionallysubstituted with one or more hydrocarbyl, halogen, ether, ester,alcohol, amide or ketone groups; and such that the fragment of theligand defined by the structure PO--R³ --OP is chiral. By thisdefinition Applicants intend that the chirality of the O-substituteddiolphosphorus ligand arise from the chirality of the parent diol HO--R³--OH. Ligands of this embodiment of the invention include ligandsderived from carbohydrates (discussed below), tartrate esters,2-2'-binaphthols, and terpene diols. Most preferred of thenoncarbohydrate diols is diisopropyltartrate.

In the preferred embodiment, the chirality of the chiral, nonracemicO-substituted diolphosphorus ligand (R¹)₂ P--R² --P(R¹)₂ is derived froma carbohydrate diol. Specifically, in this preferred embodiment, theprocess is carried out by employing chiral, nonracemic, O-substitutedcarbohydrate phosphorus ligands; including particularly pyranose,furanose, disaccharide and oligosaccharide organophosphorus ligands.Examples are represented by the formulas I-IV, ##STR6## wherein: n=0-2;

m=0-3;

R⁴ groups are independently H, hydroxy, C₁ to C₂₀ hydrocarbyl, alkoxy,aryloxy, O-substituted pyranose or O-substituted furanose;

R⁵ groups are independently H, hydroxymethyl (CH₂ OH), alkoxymethyl,aryloxymethyl, or CH₂ OP(X)₂ where X is aryl, alkoxy, or aryloxy;

R⁶ groups are independently H, C₁ to C₂₀ hydrocarbyl, acyl, or P(X)₂where X is aryl, alkoxy, or aryloxy;

R⁷ is H or CH₃ ;

and the sum total of P(X)₂ groups present in the O-substituted pyranose,furanose, dissacharide or oligosaccharide organophosphorus ligand isequal to 2. Applicants also specifically include within the carbohydrateligand compositions of the invention those carbohydrates containingprotective groups. By the term "protective group", Applicants includegroups such as ethers and esters which may function to provide chiralrecognition of the sugar molecule, and further are commonly employed toprotect the sugar molecule from nonselective reactions. Applicantsfurther intend to particularly include disaccharides formed by Joiningtwo of the structures shown in formulas I-IV through an oxygen atom atthe anomeric position of the furanose or pyranose ring. Two examples ofsuch dissacharides are shown below wherein Ph is phenyl and Ac isacetyl. ##STR7##

Most preferably, the chiral, nonracemic, organophosphorus ligand is achiral, nonracemic, O-substituted glucopyranose organophosphorus ligandof the formula V, ##STR8## wherein: R⁸ is H, hydroxy, C₁ to C₂₀hydrocarbyl, alkoxy, or aryloxy;

R⁹ is independently selected from H, C₁ to C₂₀ hydrocarbyl, acyl orP(X)₂, where X is aryl, alkoxy, aryloxy;

and the sum total of P (X) 2 groups present in the O-substitutedglucopyranose organophosphorus ligand is equal to 2.

Chiral, nonracemic O-substituted diolphosphorus ligands, includingcarbohydrate derived diolphosphorus ligands, can be prepared accordingto techniques well-known in the art. (J. Organomet. Chem., 1978, 159,C29; Tetrahedron Lett., 1978, 1635; J. Org. Chem., 1980, 45, 62; Bull.Chem. Soc. Jpn., 1986, 59, 175; J. Mol. Catal., 1986, 37, 213; J. Prakt.Chem., 1987, 329 (4), 717). In general, diol derivatives containingunprotected hydroxyl groups are treated with a P(R)₂ Cl (wherein R maygenerally be an alkyl, aryl, alkoxy, or aryloxy) reagent in the presenceof a base, such as pyridine or triethylamine, to produce the desiredphosphinite or phosphite. Some P(R)₂ Cl reagents are commerciallyavailable, such as PPh₂ Cl (Ph=phenyl). P(R)₂ Cl reagents, where R=arylor alkyl, can also be prepared in two steps by treatment of readilyavailable dialkyl phosphites, such as dibutyl phosphite, HP(O)(OBu)₂,with RMgBr followed by treatment of the resulting HP(O)R₂ product withPCl₃ (J. Am. Chem. Soc., 1951, 73, 4101; J. Am. Chem. Soc., 1952, 74,5418; J. Org. Chem., 1966, 31, 1206). P(R)₂ Cl reagents, where R=alkoxyor aryloxy, can be prepared in two steps by treatment of P (NEt₂)₃ withROH to generate P(OR)₂ (NEt₂), followed by treatment with CH₃ COCl togenerate P(OR)₂ Cl. Illustrative preparations are provided below.

For all embodiments of the invention the chiral, nonracemic nickelhydrocyanation catalyst may be prepared by mixing the zero-valent nickelsource and the chiral, nonracemic, organophosphorus ligand, preferablyin a nonpolar organic solvent such as benzene, toluene or hexane, underan inert atmosphere such as N₂ or Ar in a temperature range from 0° C.to 120° C., preferably in a temperature range from 0° C. to 80° C., andthen adding the mixture to the aromatic vinyl compound. Alternatively,the hydrocyanation catalyst may be prepared in situ by adding thezero-valent nickel source and the chiral, nonracemic, organophosphorusligand directly into the reaction mixture containing the aromatic vinylcompound.

The molar ratio of chiral, nonracemic, organophosphorus ligand to nickelmay vary between 0.01:1 to 10:1, preferably between 1:1 to 2:1, mostpreferably between 1:1 to 1.5:1.

The molar ratio of nickel to aromatic vinyl compound may vary between0.0001:1 to 1:1, preferably between 0.001:1 to 0.05:1.

The aromatic vinyl compound starting material, which is represented bythe formula Ar--CH═CH₂ may be dissolved in any organic solventcompatible with the reagents employed, preferably a nonpolar solventsuch as, but not limited to, benzene, toluene, or hexane. Alternatively,for liquid aromatic vinyl compounds, HCN may be added directly to themixture of catalyst and aromatic vinyl compound.

HCN may be added as a pure compound or as a solution in any organicsolvent compatible with the reagents employed, preferably a nonpolarsolvent such as benzene, toluene or hexane. Alternatively HCN may begenerated in situ (e.g. from cyanide salts or cyanohydrins). The amountof HCN added to the reaction process may vary from 0.01 to 10.0 molarequivalents per equivalent of the aromatic vinyl group. A minimum of 1.0equivalent of HCN is required to obtain complete conversion of the vinylequivalents in the substrate.

The hydrocyanation reaction is carried out over a temperature range from20° to 120° C., preferably 25° to 80° C., under an inert atmosphere suchas N₂ or Ar.

The Applicants note that the observed e.e.'s generally decrease as thetemperature is increased.

The enantioselective hydrocyanation reactions are generally completewithin 1-48 hours of the final HCN addition.

The preparation of optically pure(S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile is achieved using apreferred embodiment of the process for the enantioselectivehydrocyanation of an aromatic vinyl compound using a catalystcomposition comprising zero-valent nickel and a chiral, nonracemic,bidentate organophosphorus ligand of the formula (R¹)₂ P--R² --P(R¹)₂wherein the aromatic vinyl compound is 6-methoxy-2-vinylnaphthalene, thepreferred source of zero-valent nickel is Ni(COD)₂, R¹ is the aryl group3,5-bis (trifluoromethyl)phenyl, and R² is the O-substitutedβ-D-glucopyranose derivative of the formula VI ##STR9## For thepreparation of optically pure (S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile, the enantioselective hydrocyanation is preferably carriedout at 25° C. under a N₂ atmosphere using 1 to 2 molar equivalents ofHCN per molar equivalent of 6-methoxy-2-vinylnaphthalene. HCN ispreferably dissolved in a non-polar organic solvent such as toluene orbenzene and added to a mixture of the zero-valent nickel, chiral,nonracemic, bidentate organophosphorus ligand and6-methoxy-2-vinylnaphthalene in a non-polar organic solvent such asbenzene, toluene or hexane. In this preferred embodiment a molar ratiobetween 0.005:1 to 0.05:1 of nickel to aromatic vinyl compound ispreferred. A molar ratio between 1:1 to 1:2 of nickel toorganophosphorus ligand is preferred.

Using these preferred conditions an e.e. between 75-85% of the Senantiomer of 2-(6-methoxy-2-naphthalene)propionitrile and a yieldbetween 75-100% will generally be obtained. Isolation of the productnitrile can be achieved by flash column chromotagraphy of the reactionmixture on silica gel using 10% diethyl ether/hexane as eluent.Alternatively, product nitrile may precipitate from the reactionmixture. Optically pure(S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile may then be obtainedby one or two recrystallizations from an organic solvent or a mixture oforganic solvents, preferably diethyl ether/hexane mixtures. Opticallypure (S)--(-)-2-(6-methoxy-2-naphthalene)propionitrile is readilydistinguished from the racemic nitrile by its melting point (99°-100° C.as compared to 72°-74° C. for racemic nitrile) and optical rotation (α!²⁵ _(D) =-28.4±1.6°, C 0.5 in CHCl₃).

Procedures for the Preparation of Chiral, O-Substituted CarbohydratePhosphinite and Phosphite Ligands

The following procedures illustrate the preparation of the chiralligands. All reactions were carried out under a N₂ atmosphere usingstandard Schlenk techniques or a Vacuum Atmospheres Co. Drybox. With theexception of compound 1, all isolated compounds were handled and storedunder a N₂ atmosphere. Solvents were distilled and degassed prior touse.

Preparation of Bis(3,5-bis(trifluoromethyl)-phenyl)phosphineoxide(3,5-(CF₃)₂ C₆ H₃)₂ P (O) H, Compound 1

A solution of dibutylphosphite, HP(O)(OBu)₂ (0.025 mol, 4.855 g), in 5ml of Et₂ O was added dropwise by an addition funnel to a slurry of KH(0.0275 mol, 1.103 g) in 10 ml of Et₂ O (caution: H₂ evolution occurs)and stirred for 5 hours at room temperature. The reaction mixture wasfiltered to remove excess KH and washed with Et₂ O. The resultingfiltrate of KP (O)(OBu)₂ was treated dropwise with a solution of(3,5-(CF₃)₂ C₆ H₃)MgBr (0.050 mol) in about 15 ml of Et₂ O. The reactionmixture was stirred for 4 hours, quenched with 50% aqueous Na₂ HPO₄,filtered and rinsed with Et₂ O. The organic layer was separated and theaqueous layer extracted twice with Et₂ O. The organic layers werecombined, dried over Na₂ SO₄, filtered and then concentrated to drynessin vacuo. The resulting dark solids were refluxed briefly in benzene,the mother liquor filtered to remove dark solids, and the filtrateconcentrated to dryness in vacuo to give 8.72 g (74%) of the desirephosphine oxide. ³¹ P {¹ H} (C₆ D₆): 12.1 ppm, s (JPH═506 Hz, ¹ Hcoupled spectrum). ¹ H (C₆ D₆): 7.27, d, 509 Hz, 1H; 7.56, s, 2H; 7.78,d, 13.0 Hz, 4H.

Preparation of Bis(3,5-bis(trifluoromethyl)phenyl)phosphine Chloride(3,5-(CF₃)₂ C₆ H₃)₂ PCl, Compound 2

PCl₃ (3.49 g, 0.0255 mol) was added dropwise to a solution of(3,5-(CF₃)₂ C₆ H₃)₂ P(O)H,1, (8.72 g, 0.018 mol) in about 35 ml of CH₂Cl₂ and stirred at room temperature for about 1.5 hours. The reactionmixture was concentrated to an oil under high vacuum at roomtemperature, and then the product was vacuum transferred from thenonvolatile byproducts under high vacuum by heating with a heat gun.Yield 6.36 g (72%) of a white solid of about 95 mol % purity by ³¹ p and¹ H NMR spectroscopy. ³¹ P{1H} (C₆ D₆): 70.4, s. ¹ H (C₆ D₆): 7.54, s,1H; 7.66, d, 6.5 Hz.

Preparation of Phenyl2,3-bis-O-(3,5-bis(trifluoromethyl)phenyl)phosphino-4,6-O-benzylidene-.beta.-D-glucopyranoside,Compound 3 ##STR10##

A solution of (3,5-(CF₃)₂ C₆ H₃)₂ PCl, 2 (1558 g, 3.15 mmol) in about 3ml of Et₂ O was cooled to about 0° C. and then added dropwise to aslurry, previously cooled to about 0° C., of NEt₃ (0.506 g, 5.0 mmol)and phenyl 4,6-O-benzylidene-β-D-glucopyranoside in about 15 ml of Et₂O. The reaction mixture was stirred for about 1.5 hours at roomtemperature, filtered to remove HNEt₃ Cl, the solids washed with Et₂ O,and the filtrate concentrated to dryness in vacuo. The filtrate residuewas then slurried with about 20 ml of hexane for about 16 hours. Theresulting white solids were collected by filtration and dried in vacuo.Yield 1.36 g (88 %). ³¹ P{¹ H} (C₆ D₆): 108.4, s, 1P; 107.5, s, 1P. 1H(C₆ D₆): 2.980, m, 1H; 3.149, t, 9.2 Hz, 1H; 3.272, t, 10.2 Hz, 1H;3.884, d.d., 4.9, 10.4 Hz, 1H; 4.186, m, 2H; 4.690, m, 1H; 4.936, s, 1H;6.327, d, 7.9 Hz, 2H; 6.69, t, 7.3 Hz, 1H; 6.875, t, 8.0 Hz, 2H; 6.968,m, 2H; 7.049, m, 3 H; 7.353, s, 2H; 7.388, s, 2H; 7.818, m, 8H.

Preparation of(S,S)-1,2-diphenyl-1,2-O-(N,N-diethylaminophosphino)ethane, Compound 4

A solution of P (NEt₂)₃ (0.371 g, 1.5 mmol) in about 1 ml of benzene wasadded to a solution of (S,S)-hydrobenzoin (0.321 g, 1.5 mmol) in about 5ml of benzene and then refluxed for 3 hours under N₂. ³¹ P NMR analysisindicated essentially complete conversion to the desired product. ³¹ p{¹ H} (C₆ D₆): 150.5, s.

Preparation of (S,S)-1,2-diphenyl-1,2-O-(chlorophosphino)ethane,Compound 5

The sample of 4 prepared as described above was concentrated in vacuo toan oil, dissolved in about 5 ml of CH₂ Cl₂, and treated dropwise with asolution of acetyl chloride (0.130 g, 1.65 mmol) in about 1 ml of CH₂Cl₂. After 4 hours of stirring the sample was concentrated to drynessunder high vacuum. ³¹ P{¹ H} (C₆ D₆): 173.2, s.

Preparation of Phenyl2,3-bis-O-(((S,S)-1',2'-diphenyl-1',2'-O-phosphino)ethane)-4,6-O-benzylidene-β-D-glucopyranoside,Compound 6 ##STR11##

A solution of 5 in about 5 ml of CH₂ Cl₂, previously cooled to about 0°C., was added dropwise to to a solution of phenyl4,6-O-benzylidene-β-D-glucopyranoside (0.234 g, 0.68 mmol), and4-dimethylaminopyridine (0.018 g, 0.15 mmol) in about 15 ml ofpyridine/CH₂ Cl₂ (50/50 by volume), previously cooled to about 0° C. Thereaction mixture was stirred for about 16 hours and concentrated todryness in vacuo. The residue was refluxed in hot benzene, filtered toremove hydrochloride salts, and the filtrate concentrated to dryness invacuo. The residue was slurried in hexane and the resulting white solidswere filtered, washed with hexane and dried in vacuo. Yield 0.549 g(97%). ³¹ P{¹ H} (C₆ D₆): 143.4, s, 1P; 144.9, s, 1P. 1H (C₆ D₆): 3.09,m, 1H; 3.35, t, 9.7Hz, 2H; 4.00, d.d.,1H; 4.52, q., 1H; 4.64, q., 1H;4.80, m., 3H; 5.12, s, 1H; 5.22, d., 9.3 Hz, 1H; 5.40, d., 9.3 Hz, 1H;6.72, t., 1H; 6.8-7.3, m., 23H; 7.40, d., 7.2 Hz, 2H; 7.46, d., 7.2Hz,2H; 7.67, d.d., 1.9, 7.5 Hz, 2H.

Ligands B through J were made using similar procedures to thosedescribed above, or were obtained commercially.

Preparation of (C₆ H₅)₂ P!₂ -(R)--(+)-1,1'-binaphtholate (BINAP)

A glass reactor is charged with (R)--(+)-1,1'-binaphthol (1.00 g),triethylamine (3.25 cc), and anhydrous diethylether (15 cc) and cooledunder nitrogen atmosphere to -78° C. (dry ice/acetone bath). A solutionof diphenylphosphorus chloride (Ph₂ PCl) (1.25 cc) in diethyl ether (10cc) is added dropwise with stirring. The resulting suspensions isallowed to warm to room temperature and stirring continued overnight.The mixture is filtered and the filtrate evaporated to dryness undervacuum. The resulting white powder was washed with pentane to give thetitled compound, a free flowing white powder (1.58 g; 69% yield) whichwas dried under high vacuum and submitted for element carbon andhydrogen analysis. Calc'd for C₄₄ H₃₂ O₂ P₂ (MW 654); % C 80.73; % H4,89. Found % C 81.15, 80.87; % H 4.82, 4.63; % N 0.03, 0.01.

In a similar manner, chelating ligands were made fromdimethyl-D-tartrate, dimethyl-L-tartrate, diisopropyl-D-tartrate, and(+)-Pinanediol.

EXAMPLES

Enantioselective Hydrocyanation of Vinyl Aromatic Compounds for Examples1-36

Results and reaction conditions for the enantioselective hydrocyanationof vinyl aromatic compounds are shown in Tables 1, 2 and 3, except forExamples 37, 46 and 47, which are described therein. With a fewexceptions which are noted, the hydrocyanations were carried out by thedropwise addition of a toluene solution of HCN (typically 0.05 to 0.15equivalents of HCN per equivalent of vinyl aromatic compound) to abenzene or toluene solution of Ni(COD)₂ (COD═1,5-cyclooctadiene), thechiral ligand and the vinyl aromatic compound under a N₂ atmosphere.Conversions were determined by GC using a cross-linked methylsiliconecapillary column (30 m×0.530 m). E.E.'s were determined by HPLC using aBakerbond Chiral DNBPG, Chiralcel OJ or OB column: 5% i-PrOH/Hexane, 1ml/min., 40° C. HPLC samples were passed through a short pad of silicagel and eluted with 90/10 hexane/Et₂ O prior to analysis. Positive e.e.values indicate an excess of the earlier eluting enantiomer. Negativevalues indicate an excess of the later eluting enantiomer. For examplesinvolving 2-vinylnaphthalene (VN) and 6-methoxy-2-vinylnaphthalene (MVN)the earlier (+) enantiomer was determined to be the S enantiomer bycomparison to a sample enriched in the "S" enantiomer. This enrichedsample was obtained by conversion of commercially available, opticallypure S--(+)-2-(6-methoxy-2-naphthalene)propionic acid (Naproxen) intothe corresponding amide with ClO₂ Et/NH₃ in CHCl₃, followed byconversion to the nitrile with Ph₃ /CCl₄ in dichloroethane. The relativeassignments of the enantiomers derived from styrene and4-isobutylstyrene were not determined.

Procedure I

A solution of Ni(COD)₂ (0.009 g, 0.033 mmol) in about 1 ml of benzenewas added to a solution of the chiral ligand (0.042 mmol) in about 1 mlof benzene, stirred for 30 minutes and added to the vinyl aromaticcompound (0.65 mmol). The reaction mixture was brought to the specifiedtemperature and HCN (0.600 ml, 0.22M in toluene, 0.132 mmol) was addedby syringe or autopipette. The reaction mixture was analyzed by GC andHPLC after about 3-4 hours of stirring.

Procedure II

A solution of Ni(COD)₂ (0.009 g, 0.033 mmol) in about 1 ml of benzenewas added to a solution of the chiral ligand (0.066 mmol) in about 1 mlof benzene, stirred for 30 minutes and added to the vinyl aromaticcompound (0.65 mmol). The reaction mixture was brought to the specifiedtemperature and HCN (0.600 ml, 0.22M in toluene, 0.132 mmol) was addedby syringe or autopipette. The reaction mixture was analyzed by GC andHPLC.

Examples 4-5, 7, 14-17, 24, 27, 33 and 34 were carried out as describedin Procedure I.

Examples 3, 10, 20-22 and 35 were carried out as described in ProcedureII.

Example 1 was carried out as described in Procedure II except thecatalyst and ligand were dissolved in 5 ml of benzene, 3.25 mmol ofvinyl aromatic compound was used and HCN (0.22M in toluene) was added bysyringe pump at 0.5 ml/hr over 16 hours.

Example 2 was carried out as described in Procedure II except thecatalyst and ligand were dissolved in 5 ml of benzene, 3.25 mmol ofvinyl aromatic compound was used and HCN (0.22M in toluene) was added bysyringe pump at 0.25 ml/hr over 16 hours.

Example 6 was carried out as described in Procedure I except 1 mmol ofvinyl aromatic compound was used and HCN (0.22M in toluene) was added bysyringe pump at 0.25 ml/hr over 16 hours.

Example 8 was carried out as described in Procedure I except thesolution of Ni(COD)₂ and ligand in benzene was concentrated to drynessin vacuo, redissolved in about 1 ml of hexane and then added to a slurryof the vinyl aromatic compound in about I ml of hexane. HCN was added(0.123 ml, 0.132 mmol) as a 1.07M solution in toluene.

Example 9 was carried out as described in Procedure I except HCN wasadded in three 1.200 ml increments and analyzed after each addition. Nochange in e.e. was observed as the conversion increased.

Examples 11, 12, 19, 25, 26, 29 and 30 were carried out as described inProcedure I except HCN was added (0.123 ml, 0.132 mmol) as a 1.07Msolution in toluene.

Examples 13 and 28 were carried out as described in Procedure I excepthexane was substituted for benzene and HCN was added (0.123 ml, 0.132mmol) as a 1.07M solution in toluene.

Example 18 was carried out as described in Procedure II except 0.013mmol of Ni(COD)₂ (0.004 g) and 0.026 mmol of chiral ligand (0.020 g) in5 ml of benzene were used and 0.236 ml of HCN was added (0.22M intoluene).

Example 23 was carried out as described in Procedure I except 0.033 mmolof the chiral ligand was used.

Example 31 was carried out as described in Procedure I except 0.020 mmolof Ni(COD)₂ and 0.030 mmol of chiral ligand were used.

Example 32 was carried out as described in Procedure II except 0.073mmol of the chiral ligand was used.

Example 36 was carried out as described in Procedure II except 0.618 mlof HCN was added.

Example 37 Enantioselective Hydrocyanation at High Conversion and Low NiLoading

Ni(COD)₂ (0.325 ml of a 0.01M solution in benzene, 0.00325 mmol) and thechiral ligand 3 (0.422 ml of a 0.01M solution in benzene, 0.00423 mmol)were combined with 6-methoxy-2-vinylnaphthalene (0.120 g, 0.65 mmol) inhexane as described in Procedure I. A total of 2.065 ml of 1.07M HCN intoluene was added dropwise by autopipette and the resulting reactionmixture was analyzed by GC and HPLC after about 3-4 hours of stirring.Conversion=93%; E.E.=83%.

Examples 38 to 45 Enantioselective Hydrocyanation with Non-CarbohydrateChiral Diolphosphorus Ligands

A glass vial (4 cc) was charged with P(O-o-tolyl)₃ !₂ (C₂ H₄)Ni(O) (0.10g), (C₆ H₅)₂ P!₂ --(R)--(+)-1,1'-binaphtholate (F) (0.08 g),2-vinylnaphthalene (0.25 g), and toluene (3 cc) under nitrogenatmosphere and sealed with a septurn cap. Aliquots of liquid HCN (5microliters) were added at 30 minute intervals until no further reactionwas observed by gas chromatographic analysis. Conversion=75%; E.E.=9.6%.

Examples 39-45 were carried out as described in Example 38 using thereagent amounts and conditions detailed in Table 3.

Example 46 Hydrocyanation of Styrene

A mixture of 1.5 g (+) Diop(2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane,Aldrich Chemical Co.), 300 mg NiI₂, 300 mg zinc dust, 2 ml commercialstabilized styrene, and 2 ml acetonitrile was stirred at 80° for 5 hr.then 250 μl HCN/CH₃ CN (11N) was added overnight by syringe pump. Afteraddition of 2 ml styrene, 1 ml CH₃ CN and ca. 100 mg zinc dust another400 μl HCN/CH₃ CN was added during eight hours. After addition of 4 mlstyrene and 100 mg zinc addition of HCN/CH₃ CN at 50 μl/hr was continuedovernight. The mixture was then diluted with 50 ml heptane and 25 mlether. The mixture was filtered and the filtrate was concentrated to anoil which was diluted with an equal volume of toluene. The VPC analysisindicated that the two isomeric products PhCH(CN)CH₃ and PhCH₂ CH₂ CNhad been formed in approximately equal amounts. The PhCH(CN)CH₃ wasisolated by preparative VPC as described above to give 120 mg .sup. α!D²⁵ +1.1° C₅.5 % in CD₃ CN. An e.e. of about 10% is estimated based onthe reported .sup. α! D²⁵ value of 10° for the pure isomer. The 1H nmrspectrum was as expected for PhCH(CN)CH₃. The major product wasapparently styrene polymer which hampered the isolation of the nitrileproducts.

Example 47 Preparation of Optically Pure(S)--(-)2-(6-methoxy-2-naphthalene)propionitrile

A solution of Ni(COD)₂ (0.002 g, 0.0065 mmol) in about 1 ml of benzenewas added to a solution of the chiral ligand phenyl2,3-bis-O-(3,5-bis(trifluoromethyl)phenyl)phosphino-4,6-O-benzylidene-β-D-glucopyranoside, 3, (0.011 g, 0.0085 mmol) in about1 ml of benzene, stirred for 30 minutes and added to the vinyl aromaticcompound 6-methoxy-2-vinylnaphthalene (0.120 g, 0.65 mmol). MeN (1.3 ml,1.0M in toluene, 1.3 mmol) was added by syringe. The reaction mixturewas analyzed by GC after 1 hour of stirring, then concentrated todryness in vacuo and analyzed by HPLC. Conversion=85%/e.e.=78%. Theproduct nitrile was isolated by flash chromatography (silica gel, 1×12cm column) using 10% diethyl ether/90% hexane as eluent. Isolated yield86 mg. Recrystallization from about 20 ml of boiling 10% diethylether/hexane afforded 65 mg of nitrile with an e.e. of 89%. A secondrecrystallization from the same solvent mixture afforded 28 mg ofnitrile with an e.e. >99% (melting point=99°-100° C. and α!²⁵ _(D)=-28.4°±1.6°, C 0.5 in CHCl₃).

Tables

For the following tables and structures, Ph means phenyl, Ac meansacetyl, Me means methyl, and Et means ethyl. ##STR12##

                                      TABLE 1    __________________________________________________________________________    Asymmetric Hydrocyanation of 2-Vinylnaphthalene (VN),    6-Methoxy-2-vinylnaphthalene (MVN), 4-Isobutyl-styrene    (IBS) or Styrene Using Glucopyranoside Ligand A                                                    Conv.                                                        E.E.    Ex.       R.sup.10          R.sup.11 R.sup.12                                        L:Ni                                           Substrate                                                T (°C.)                                                    (%) (%)    __________________________________________________________________________     1 PhO               Ph.sub.2 P       2:1                                           VN   80  43  33     2 PhO               Ph.sub.2 P       2:1                                           VN   25  3   47     3 PbO               Ph.sub.2 P       2:1                                           MVN  25  9   40     4 PhO               (3-CF.sub.3 C.sub.6 H.sub.4).sub.2 P                                        1.3:1                                           VN   25  8   71     5 PhO               (3-CF.sub.3 C.sub.6 H.sub.4).sub.2 P                                        1.3:1                                           MVN  25  7   76     6 PhO               (3-CF.sub.3 C.sub.6 H.sub.4).sub.2 P                                        1.3:1                                           MVN  60  23  48     7 PhO               (3,5-(CF.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           MVN  20  5   75     8 PhO               (3,5-(CF.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           MVN  25  8   83     9 PhO               (3,5-(CF.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           VN   25  40  78    10 PhO               (EtO).sub.2 P    2:1                                           VN   25  6   18    11 PhO               (3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           MVN  25  13  16    12 PhO               (3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           VN   25  12  25    13 PhO               (3,5-(CH.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           VN   25  9   43    14 PhO                                        1.3:1                                           VN   25  2   49    15 PhO                          ##STR13##     1.3:1                                           VN   25  4   -13    16 PhO                          ##STR14##     1.3:1                                           VN   25  1   60    17 PhO                          ##STR15##     1.3:1                                           VN   25  1   26    18 PhCH(CN)O         Ph.sub.2 P       2:1                                           VN   25  3   46    19 CH.sub.3 O        Ph.sub.2 P     1.3:1                                           MVN  25  8   40    20        ##STR16##        Ph.sub.2 P       2:1                                           VN   25  3   52    21        ##STR17##        Ph.sub.2 P       2:1                                           VN   80  1   50    22        ##STR18##        Ph.sub.2 P       2:1                                           VN   25  10  51    23        ##STR19##        Ph.sub.2 P       1:1                                           VN   25  8   45    24        ##STR20##        Ph.sub.2 P     1.3:1                                           VN   25  10  49    25        ##STR21##        Ph.sub.2 P     1.3:1                                           VN   25  7   43    26        ##STR22##        Ph.sub.2 P     1.3:1                                           MVN  25  8   36    27        ##STR23##        (3-CF.sub.3 C.sub.6 H.sub.4).sub.2 P                                        1.3:1                                           MVN  25  6   22    28 PhO               Ph.sub.2 P     1.3:1                                           IBS  25  7   10    29 PhO               (3,5-(CF.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           IBS  25  9   -51    30 PhO               (3,5-(CF.sub.3).sub.2 C.sub.6 H.sub.3).sub.2                                        1.3:1                                           Styrene                                                25  7   -10    __________________________________________________________________________     ##STR24##

                                      TABLE 2    __________________________________________________________________________    Asymmetric Hydrocyanation Using Ligands (L) B-E    Ex.       L R.sup.13 R.sup.14  L:Ni                               Substrate                                    T (°C.)                                        Conv. (%)                                              E.E.    __________________________________________________________________________    31 B --       --        1.5:1                               VN   25  10    -30    32 C --       --        2.2:1                               MVN  25   6    10    33 D Ph.sub.2 P--                  Ph.sub.2 P--                            1.3:1                               VN   25  11    -8    34 D (3-CF.sub.3 C.sub.6 H.sub.4).sub.2 P--                  (3-CF.sub.3 C.sub.6 --H.sub.4).sub.2 P--                            1.3:1                               MVN  25  13    -7    35 E Ph.sub.2 P--                  PhCH.sub.2 O--                              2:1                               VN   25   1    6    36 E PhCH.sub.2 O--                  Ph.sub.2 P--                              2:1                               MVN  25  10    14    __________________________________________________________________________     ##STR25##

                  TABLE 3    ______________________________________    Asymmetric Hydrocyanation of 2-Vinylnaphthalene (VN)    using Non-carbohydrate, Chiral Organophosphorus    Ligands (L), F-J and BINAP         L           Ni      VN    T     Conv.    Ex.  (mmol)      (mmol)  (mmol)                                   (°C.)                                         (%)   E.E.    ______________________________________    38   F, .12      .13     1.6   25    75    9.6    39   G, .37      .13     1.0   75    >80   -18    40   H, .37      .13     1.0   75    >80   18    41   H, .55      .19     1.6   80    --    25    42   I, .17       .063    .65  75    >90   -22.4    43   J, .37      .13     1.0   20    7     6.4    44   (+)BINAP, .14                      .063    .65  20    >70   21.5    45   (-)BINAP, .15                      .063    .65  20    >80   -21.2    ______________________________________

We claim:
 1. A chiral, nonracemic, bidentate organophosphorus ligand ofthe formula:

    (R.sup.1).sub.2 --P--O--R.sup.3 --O--P--(R.sup.1).sub.2

wherein each R¹ is 3,5-bis(trifluoromethyl)phenyl; and R³ is a C₄ to C₄₀dideoxycarbohydrate, optionally substituted with one or morehydrocarbyl, halogen, ether, ester, alcohol, amide or ketone groups. 2.The ligand of claim 1 wherein R³ is a dideoxymonosaccharide,dideoxydisaccharide or dideoxyoligosaccharide.
 3. The ligand of claim 1wherein R³ is a dideoxyhexose.
 4. The ligand of claim 3 wherein R³ is adideoxyglucose.
 5. The ligand of claim 3 wherein R³ is adideoxygalactose.
 6. The ligand of claim 1 wherein R³ is adideoxypentose.
 7. The ligand of claim 2 wherein R³ is a dideoxylactose.8. The ligand of claim 2 wherein R³ is a dideoxytrehalose.
 9. The ligandof claim 1 wherein the ligand is phenyl2,3-bis-O-(3,5-bis(trifluoromethyl)phenyl)-phosphine-4,6-O-benzylidene-.beta.-D-glucopyranoside.